nach oben

Erschienen in:

24.01.2022 | Original Article

Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma

verfasst von: Taichi Kadonaga, Tomohiko Sakabe, Yoshiteru Kidokoro, Tomohiro Haruki, Kanae Nosaka, Hiroshige Nakamura, Yoshihisa Umekita

Erschienen in: Virchows Archiv | Ausgabe 4/2022

Einloggen, um Zugang zu erhalten

Abstract

Lung adenocarcinoma (LUAD) shows heterogeneous morphological features and the stepwise progression from adenocarcinoma in situ to minimally invasive adenocarcinoma to invasive LUAD. Although multiple genetic alterations have been linked to the progression, the differences between the gene expression profiles of non-invasive lesions (non-ILs) and adjacent histologically normal lung (aNL) tissues within invasive LUAD have not been investigated. Herein, we analyzed differentially expressed genes (DEGs) specific to early-stage carcinogenesis in LUAD. Invasive LUAD tissue samples containing both non-ILs and aNL tissues were obtained from seven patients with pathological stage I LUAD, and each component was subjected to microdissection. Gene expression profiles of each component were determined using targeted RNA-sequencing. In total, 2536 DEGs, including 863 upregulated and 1673 downregulated genes, were identified in non-ILs. In non-ILs, the expression of SLC44A5, a choline transporter-like protein-coding gene, was significantly upregulated, and that of TMEM100, a gene encoding a transmembrane protein, was significantly downregulated. Reportedly, SLC44A5 plays an important role in the development and progression of hepatocellular carcinoma, whereas TMEM100 functions as a tumor suppressor in non-small cell lung cancer. Gene set enrichment analysis showed that DEGs in non-ILs were negatively enriched in cell death and immune response. Immunohistochemical analysis revealed that increased SLC44A5 expression and decreased TMEM100 expression were maintained in ILs. A protein–protein interaction (PPI) network analysis identified several upregulated and downregulated hub genes with high degrees in non-ILs. In conclusion, several new DEGs and key PPI network hub genes were identified in non-ILs, contributing to understanding of early-stage carcinogenesis in LUAD.

Nur mit Berechtigung zugänglich

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660CrossRefPubMed

Travis WD, Brambilla E, Bruke AP, Marx A, Nicholson AG (2015) WHO classification of tumors of the lung, pleura, thymus, and heart, 4th edn. IARC Press France, Lyon, pp 26–30

Hu X, Fujimoto J, Ying L et al (2019) Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma. Nat Commun 10:2978. https://doi.org/10.1038/s41467-019-10877-8CrossRefPubMedPubMedCentral

Pao W, Hutchinson KE (2012) Chipping away at the lung cancer genome. Nat Med 18:349–351. https://doi.org/10.1038/nm.2697CrossRefPubMed

The Cancer Genome Atlas Research Network (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543–550. https://doi.org/10.1038/nature13385CrossRefPubMedCentral

Desai TJ, Brownfield DG, Krasnow MA (2014) Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 507:190–194. https://doi.org/10.1038/nature12930CrossRefPubMedPubMedCentral

Ferone G, Lee MC, Sage J, Berns A (2020) Cells of origin of lung cancers: lessons from mouse studies. Genes Dev 34:1017–1032. https://doi.org/10.1101/gad.338228.120CrossRefPubMedPubMedCentral

Murphy SJ, Wigle DA, Lima JF et al (2014) Genomic rearrangements define lineage relationships between adjacent lepidic and invasive components in lung adenocarcinoma. Cancer Res 74:3157–3167. https://doi.org/10.1158/0008-5472.can-13-1727CrossRefPubMedPubMedCentral

Vinayanuwattikun C, Le Calvez-Kelm F, Abedi-Ardekani B et al (2016) Elucidating genomic characteristics of lung cancer progression from in situ to invasive adenocarcinoma. Sci Rep 6:31628. https://doi.org/10.1038/srep31628CrossRefPubMedPubMedCentral

10.

Nishimura T, Nakamura H, Tan KT et al (2020) A proteogenomic profile of early lung adenocarcinomas by protein co-expression network and genomic alteration analysis. Sci Rep 10:13604. https://doi.org/10.1038/s41598-020-70578-xCrossRefPubMedPubMedCentral

11.

Qian J, Zhao S, Zou Y, Rahman SMJ, Senosain MF, Stricker T, Chen H, Powell CA, Borczuk AC, Massion PP (2020) Genomic understandings of tumor behavior in in situ and early lung adenocarcinoma. Am J Respir Crit Care Med 201:697–706. https://doi.org/10.1164/rccm.201902-0294ocCrossRefPubMedPubMedCentral

12.

Chen H, Carrot-Zhang J, Zhao Y et al (2019) Genomic and immune profiling of pre-invasive lung adenocarcinoma. Nat Commun 10:5472. https://doi.org/10.1038/s41467-019-13460-3CrossRefPubMedPubMedCentral

13.

Kato Y, Nakamura H, Tojo H et al (2015) A proteomic profiling of laser-microdissected lung adenocarcinoma cells of early lepidic-types. Clin Transl Med 4:64. https://doi.org/10.1186/s40169-015-0064-3CrossRefPubMed

14.

Kidokoro Y, Sakabe T, Haruki T, Kadonaga T, Nosaka K, Nakamura H, Umekita Y (2020) Gene expression profiling by targeted RNA sequencing in pathological stage I lung adenocarcinoma with a solid component. Lung Cancer 147:56–63. https://doi.org/10.1016/j.lungcan.2020.06.035CrossRefPubMed

15.

Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, Nicholson AG, Groome P, Mitchell A, Bolejack V (2016) The IASLC lung cancer staging project: TNM classification for lung cancer. J Thorac Oncol 11:39–51. https://doi.org/10.1016/j.jtho.2015.09.009CrossRefPubMed

16.

Subramanian A, Tamayo P, Mootha VK et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550. https://doi.org/10.1073/pnas.0506580102CrossRefPubMedPubMedCentral

17.

Mootha VK, Lindgren CM, Eriksson KF et al (2003) PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273. https://doi.org/10.1038/ng1180CrossRefPubMed

18.

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504. https://doi.org/10.1101/gr.1239303CrossRefPubMedPubMedCentral

19.

Assenov Y, Ramírez F, Schelhorn SE, Lengauer T, Albrecht M (2008) Albrecht, computing topological parameters of biological networks. Bioinformatics 24:282–284. https://doi.org/10.1093/bioinformatics/btm554CrossRefPubMed

20.

Basnet H, Tian L, Ganesh K, Huang YH, Macalinao DG, Brogi E, Finley LW, Massagué J (2019) Flura-seq identifies organ-specific metabolic adaptations during early metastatic colonization. Elife 8:e43627. https://doi.org/10.7554/elife.43627CrossRefPubMedPubMedCentral

21.

Pyo KH, Kim JH, Lee JM, Kim SE, Cho JS, Lim SM, Cho BC (2019) Promising preclinical platform for evaluation of immuno-oncology drugs using Hu-PBL-NSG lung cancer models. Lung Cancer 127:112–121. https://doi.org/10.1016/j.lungcan.2018.11.035CrossRefPubMed

22.

Szklarczyk D, Morris JH, Cook H et al (2017) The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 45:D362–D368. https://doi.org/10.1093/nar/gkw937CrossRefPubMed

23.

Chen YJ, Roumeliotis TI, Chang YH et al (2020) Proteogenomics of non-smoking lung cancer in East Asia delineates molecular signatures of pathogenesis and progression. Cell 182:226-244.e217. https://doi.org/10.1016/j.cell.2020.06.012CrossRefPubMed

24.

Gillette MA, Satpathy S, Cao S et al (2020) Proteogenomic characterization reveals therapeutic vulnerabilities in lung adenocarcinoma. Cell 182:200-225.e235. https://doi.org/10.1016/j.cell.2020.06.013CrossRefPubMedPubMedCentral

25.

Inazu M (2014) Choline transporter-like proteins CTLs/SLC44 family as a novel molecular target for cancer therapy. Biopharm Drug Dispos 35:431–449. https://doi.org/10.1002/bdd.1892CrossRefPubMed

26.

Peng GZ, Ye QF, Wang R, Li MX, Yang ZX (2016) Knockdown by shRNA identifies SLC44A5 as a potential therapeutic target in hepatocellular carcinoma. Mol Med Rep 13:4845–4852. https://doi.org/10.3892/mmr.2016.5136CrossRefPubMed

27.

Moon EH, Kim YS, Seo J, Lee S, Lee YJ, Oh SP (2015) Essential role for TMEM100 in vascular integrity but limited contributions to the pathogenesis of hereditary haemorrhagic telangiectasis. Cardiovasc Res 105:353–360. https://doi.org/10.1093/cvr/cvu260CrossRefPubMed

28.

Frullanti E, Colombo F, Falvella FS et al (2012) Association of lung adenocarcinoma clinical stage with gene expression pattern in noninvolved lung tissue. Int J Cancer 131:E643–E648. https://doi.org/10.1002/ijc.27426CrossRefPubMed

29.

Han Z, Wang T, Han S et al (2017) Low-expression of TMEM100 is associated with poor prognosis in non-small cell lung cancer. Am. J. Trans. Res 9:2567–2578. http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5446537/

30.

He Q, Dong Y, Zhu Y, Ding Z, Zhang X, Wang Z, Ai R, He Y (2021) TMEM100 induces cell death in non-small cell lung cancer via the activation of autophagy and apoptosis. Oncol Rep 45:63. https://doi.org/10.3892/or.2021.8014CrossRefPubMed

31.

Zhuang J, Huang Y, Zheng W, Yang S, Zhu G, Wang J, Lin X, Ye J (2020) TMEM100 expression suppresses metastasis and enhances sensitivity to chemotherapy in gastric cancer. Biol Chem 401:285–296. https://doi.org/10.1515/hsz-2019-0161CrossRefPubMed

32.

Chen Y, Hu R, Li X, Shi Z, Tian H, Feng J, Yu S (2020) B7–H4 and HHLA2, members of B7 family, are aberrantly expressed in EGFR mutated lung adenocarcinoma. Pathol Res Pract 216:153134. https://doi.org/10.1016/j.prp.2020.153134CrossRefPubMed

33.

Cheng H, Borczuk A, Janakiram M, Ren X, Lin J, Assal A, Halmos B, Perez-Soler R, Zang X (2018) Wide expression and significance of alternative immune checkpoint molecules, B7x and HHLA2, in PD-L1-Negative Human Lung Cancers. Clin Cancer Res 24:1954–1964. https://doi.org/10.1158/1078-0432.Ccr-17-2924CrossRefPubMedPubMedCentral

34.

Cheng H, Janakiram M, Borczuk A, Lin J, Qiu W, Liu H, Chinai JM, Halmos B, Perez-Soler R, Zang X (2017) HHLA2, a new immune checkpoint member of the B7 family, is widely expressed in human lung cancer and associated with EGFR mutational status. Clin Cancer Res 23:825–832. https://doi.org/10.1158/1078-0432.Ccr-15-3071CrossRefPubMed

35.

Zhao R, Chinai JM, Buhl S et al (2013) HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function. Proc Natl Acad Sci 110:9879–9884. https://doi.org/10.1073/pnas.1303524110CrossRefPubMedPubMedCentral

36.

Kai Y, Amatya VJ, Kushitani K, Kambara T, Suzuki R, Tsutani Y, Miyata Y, Okada M, Takeshima Y (2019) Mucin 21 is a novel, negative immunohistochemical marker for epithelioid mesothelioma for its differentiation from lung adenocarcinoma. Histopathology 74:545–554. https://doi.org/10.1111/his.13775CrossRefPubMed

37.

Kataoka T, Okudela K, Nakashima Y et al (2019) Unique expression profiles of mucin proteins in interstitial pneumonia-associated lung adenocarcinomas. Histol Histopathol 34:1243–1254. https://doi.org/10.14670/hh-18-114CrossRefPubMed

38.

Yoshimoto T, Matsubara D, Soda M et al (2019) Mucin 21 is a key molecule involved in the incohesive growth pattern in lung adenocarcinoma. Cancer Sci 110:3006–3011. https://doi.org/10.1111/cas.14129CrossRefPubMedPubMedCentral

39.

Sakamoto H, Shimizu J, Horio Y, Ueda R, Takahashi T, Mitsudomi T, Yatabe Y (2007) Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas. J Pathol 212:287–294. https://doi.org/10.1002/path.2165CrossRefPubMed

40.

Yoshida Y, Shibata T, Kokubu A, Tsuta K, Matsuno Y, Kanai Y, Asamura H, Tsuchiya R, Hirohashi S (2005) Mutations of the epidermal growth factor receptor gene in atypical adenomatous hyperplasia and bronchioloalveolar carcinoma of the lung. Lung Cancer 50:1–8. https://doi.org/10.1016/j.lungcan.2005.04.012CrossRefPubMed

41.

Soh J, Toyooka S, Ichihara S et al (2008) Sequential molecular changes during multistage pathogenesis of small peripheral adenocarcinomas of the lung. J Thorac Oncol 3:340–347. https://doi.org/10.1097/jto.0b013e318168d20aCrossRefPubMedPubMedCentral

42.

Sivakumar S, Lucas FAS, McDowell TL et al (2017) Genomic landscape of atypical adenomatous hyperplasia reveals divergent modes to lung adenocarcinoma. Cancer Res 77:6119–6130. https://doi.org/10.1158/0008-5472.can-17-1605CrossRefPubMedPubMedCentral

Titel: Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma
verfasst von: Taichi Kadonaga
Tomohiko Sakabe
Yoshiteru Kidokoro
Tomohiro Haruki
Kanae Nosaka
Hiroshige Nakamura
Yoshihisa Umekita
Publikationsdatum: 24.01.2022
Verlag: Springer Berlin Heidelberg
Erschienen in: Virchows Archiv / Ausgabe 4/2022
Print ISSN: 0945-6317
Elektronische ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-021-03250-y

Springer Medizin

Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma

Abstract

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2022

Recommendations for diagnosing STIC: a systematic review and meta-analysis

Myxoid type and non-myxoid type of intimal sarcoma in large vessels and heart: review of histological and genetic profiles of 20 cases

POU2F3 beyond thymic carcinomas: expression across the spectrum of thymomas hints to medullary differentiation in type A thymoma

Does PAX7 and NKX2.2 immunoreactivity in Ewing sarcoma have prognostic significance?

The OLGA-OLGIM staging and the interobserver agreement for gastritis and preneoplastic lesion screening: a cross-sectional study

Distinctive patterns of marrow involvement by classic Hodgkin lymphoma are clues for diagnosis and subtyping

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie